Abstract
Antiestrogens such as tamoxifen (TAM) provided a successful treatment for estrogen receptor (ER)-positive breast cancer for the past four decades. However, most breast tumors are eventually resistant to TAM therapy. The molecular mechanisms underlying TAM resistance have not been well established. Recently, we reported that breast cancer patients with tumors expressing high concentrations of ER-α36, a variant of ER-α, benefited less from TAM therapy than those with low concentrations of ER-α36, suggesting that increased ER-α36 concentration is one of the underlying mechanisms of TAM resistance. Here, we investigated the function and underlying mechanism of ER-α36 in TAM resistance. We found that TAM increased ER-α36 concentrations, and TAM-resistant MCF7 cells expressed high concentrations of ER-α36. In addition, MCF7 cells with forced expression of recombinant ER-α36 and H3396 cells expressing high concentrations of endogenous ER-α36 were resistant to TAM. ER-α36 down-regulation in TAM-resistant cells with the short hairpinRNA method restored TAM sensitivity. We also found that TAM acted as a potent agonist by activating phosphorylation of the AKT kinase in ER-α36-expressing cells. Finally, we found that cells with high concentration of ER-α36 protein were hypersensitive to estrogen, activating ERK phosphorylation at picomolar range. Our results thus demonstrated that elevated ER-α36 concentration is one of the mechanisms by which ER-positive breast cancer cells escape TAM therapy and provided a rational to develop novel therapeutic approaches for TAM-resistant patients by targeting ER-α36.
Highlights
Antiestrogens such as tamoxifen (TAM) provided a successful treatment for estrogen receptor (ER)-positive breast cancer for the past four decades
The steady state concentration of ER-␣36 protein in MCF7 cells treated with 1M TAM for different time periods or different concentrations of TAM was examined with Western blot analysis
TAM therapy is the most effective treatment for advanced ER-positive breast cancer, but its effectiveness is limited by high rate of de novo resistance and resistance acquired during treatment
Summary
Antiestrogens such as tamoxifen (TAM) provided a successful treatment for estrogen receptor (ER)-positive breast cancer for the past four decades. We reported that breast cancer patients with tumors expressing high concentrations of ER-␣36, a variant of ER-␣, benefited less from TAM therapy than those with low concentrations of ER-␣36, suggesting that increased ER-␣36 concentration is one of the underlying mechanisms of TAM resistance. Our results demonstrated that elevated ER-␣36 concentration is one of the mechanisms by which ER-positive breast cancer cells escape TAM therapy and provided a rational to develop novel therapeutic approaches for TAM-resistant patients by targeting ER-␣36. We found that the breast cancer patients with tumors expressing high concentrations of ER-␣36 benefited less from TAM therapy than those with low concentrations of ER-␣36 [16], suggesting that increased ER-␣36 concentration is one of the underlying mechanisms of TAM resistance. We reported that ER-␣36 is able to mediate agonist activity of TAM and ICI 182, 780 [17, 18], such as activation of the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) and the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways, indicating that these antiestrogens may loss their growth-inhibitory activities in cells with increased ER-␣36 expression
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